HIVVaccine Research & Development
Prof. Omu Anzala
KAVIDepartment of Medical Microbiology
School of Medicine University of Nairobi
A DECADE OF VACCINES
What is a “Vaccine”• The term vaccine derives
from Edward Jenner's 1796 use of the term cow pox (Latin) variola vaccinæ, adapted from the Latin vaccīn-us, from vacca cow), which, when administered to humans, provided them protection against smallpox
A Decade of Vaccines
Global Commitment to:• Increase uptake of the current childhood vaccines.• Increase the use of underused vaccines • Accelerate research & development of 6 new vaccines( diarrhea & pneumonia, TB, Malaria and HIV vaccines)
Is the discovery of an HIV vaccine possible?
Basic and Epidemiology research in HIV/AIDS has been pointing to this fact.
RV144 trial in Thailand demonstrated for the first time modest protection against HIV infection.(Canary-pox-vector prime plus protein-subunit boost)
Discovery of potent and broadly neutralizing antibodies
RV 144 Study Vaccines
• ALVAC®-HIV (vCP1521) • Recombinant canarypox vector vaccine genetically
engineered to express HIV-1 gp120 (subtype E: 92TH023) linked to the transmembrane anchoring portion of gp41 (subtype B: LAI), and HIV-1 gag and protease (subtype B: LAI).
• AIDSVAX® B/E• Bivalent HIV gp120 envelope glycoprotein vaccine
containing a subtype E envelope from the HIV-1 strain CM244 and a subtype B envelope from the HIV-1 strain MN.
RV 144 The Analyses
• - the intention-to-treat and per-protocol analyses,
• showed vaccine efficacies of 26.4% (P = 0.08)• and 26.2% (P = 0.16), respectively. • a possible, albeit modest,protection
TARGET CELLEFFECTOR CELL
antigen
antibody
Fcreceptors (CD16, CD32, CD64)
granules
TARGET CELLEFFECTOR CELL
antigen
antibody
Fcreceptors (CD16, CD32, CD64)
granules
The ADCC mechanism: bridging the gap between innate and adaptive immunity
New and exciting discovery• Broadly neutralizing antibodies.• Revealed vulnerable targets on the virus that
are now being exploited for vaccine design.
CD4bs“b12”
MPER“2F5” and
4E10”
Glycan shield
“2G12”Cell Membrane
V3
Viral Membrane
gp41
gp120
CD4
Wyatt and Sodroski Science 1998Huang et al Science 2005Phogat, Wyatt Curr Pharm Design 2007
CCR5 target
Antibody Attack on Targets: What we knew and what’s NEW
“Trimer”“PG9” and “PG16”
NEW
HIV Life Cycle & Vaccine Design
Cell Mediated Immunity
Neutralizing Antibodies
HIV Vaccine Clinical ResearchIAVI 002(2001)
IAVI 004(2002)
IAVI 008(Roll over)
IAVI 010(2003)
V001(2006)
Candidate vaccine
DNA MVA DNA+MVA DNA+MVA Multi-cladeDNA/Ad5
Sample Size 18 18 10 70 57
Enrolled 15:3(M:F)
16:2(M:F)
10 58:12(M:F)
36:21(M:F)
Recruitment rate (no/month)
4.5 4.5 10 12 14
Retention rate
94.4%(17/18)
94.4%(17/18)
100% 98.6%(69/70)
98.2%(56/57)
Vaccine Research On going Vaccine trials at KAVI
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Ongoing Phase 1 clinical trialsPaedVac • Funded by EDCTP• MVA + EPI vaccination vs EPI vaccination (alone)• Safety, immunogenicity & interference with EPI
vaccines• Infants vaccinated at 20 weeks - single IM injection• Immunogenicity - ELISPOT & Cultured ELISPOT• Gambia trial over (48 infants) - data being analyzed• Nairobi trial (63/72 infants randomized)• Both sites, no vaccine related SAE• Immunogenicity data not yet out• Antibody titres to EPI being conducted
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Ongoing Phase 1 clinical trialsProtocol B002• Recombinant Fusion protein (F4co) in adjuvant
(ASO1B or ASO1E) + replication incompetent Ad35-GRIN
• F4co [p24-RT-Nef-p17 of HIV-1clade B Gag, Pol, Nef)]• Ad35-GRIN [with HIV-1 clade A gag, RT, integrase, nef)• Phase 1, double blind, randomized placebo controlled • 140 participants (112 vaccine/28 placebo)• Ages 18-40 yrs• Low risk, healthy, HIV –ve, Ad35 antibodies -ve• Multisite study – Kenya, Uganda, Zambia
15
Ongoing Phase 1 clinical trialsProtocol B003
Different combinations of recombinant Ad26 vector & recombinant Ad35 (HIV-1 sub-type A env gene)
Heterologous or homologous 212 to be enrolled Multi-centre – Boston (USA), Rwanda, S/Africa KAVI-Kangemi recruiting Screened 85 Enrolled 34
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What are the challenges• The virus impairs the immune systems• Viral diversity • The correlates of immunity or protection not fully
Mechanism of ActionVaccines:
Death Exposure Infection Disease
Recovery
Balancing safety and efficacy in HIV vaccine design
The Questions ??
Would an HIV vaccine be useful if it was less than 100% effective?
Would a vaccine still be needed if current prevention programs and antiretroviral therapy (ART) are significantly expanded while the vaccine is still being developed?
Would a vaccine result in cost-savings?
Vaccines can take decades to develop
Measles
Hepatitis B
Human papilloma virus(cervical cancer)
Rotavirus(diarrheal disease)
Varicella zoster(chickenpox)
Pertussis(whooping cough)
Polio
Haemophilus influenza
Typhoid
Malaria
Human immunodeficiency virus(HIV/AIDS)
INFECTIOUS AGENT (Disease)
AGENT LINKEDTO DISEASE IN …
VACCINE LICENSEDIN U.S. IN …
1953
1965
1884
1973
1953
1906
1908
1889
Early ’80sto mid-’90s
1893
1983
1963
1981
2006
2006
1995
1948
1955
1981
1989
—
—
YEARSELAPSED
10
16
12-25
33
42
42
47
92
105
116
28